Advances In Allergen Immunotherapy Research Articles

Advances in allergen immunotherapy for asthma.

Allergen immunotherapy (AIT) is a well-known disease-modifying intervention for allergic diseases. Its benefit in allergic asthma, ranging from prevention to facilitating asthma control, is yet to be clarified. In 2017, following several well-designed randomised controlled trials (RCTs) with house-dust mites (HDM) sublingual (SLIT) tablets in asthma, global initiative for asthma (GINA) guidelines highlighted the need to treat the allergic component of asthma. In 2019, the European Academy of Allergy and Clinical Immunology published the first comprehensive guidelines for HDM AIT in allergic asthma, formulating separate recommendations for subcutaneous, SLIT drops, and SLIT tablets. Significant steps were undertaken in understanding the mechanisms of allergic asthma, facilitating the stratified approach for selecting responders and in translating the immune-modulation effect in achieving long-term control of the chronic inflammation in asthma. Currently existing guidelines recommend AIT as a therapeutic option in controlled or partially controlled HDM allergic asthma. Limited data are available for pollen, molds and pets, as well as for the severe allergic asthma population. The challenge for the future research will be to clarify the subendotypes of allergic asthma responding to AIT, the mechanisms facilitating its' preventive and disease-modifying effect, the optimal duration of the treatment, and route of administration.

Perspectives in allergen immunotherapy: 2017 and beyond

The Future of the Allergists and Specific Immunotherapy (FASIT) workshop provides a regular platform for global experts from academia, allergy clinics, regulatory authorities and industry to review developments in the field of allergen immunotherapy (AIT). The most recent meeting, held in February 2017, had two main themes: advances in AIT and hot topics in AIT from the regulatory point of view. The first theme covered opportunities for personalized AIT, advances in adjuvants and delivery systems, and the development of new molecules and future vaccines for AIT. Key topics in the second part of the meeting were the effects of the enactment of European Directive 2001/83 on the availability of allergens for therapy and diagnosis across the EU, the challenges of conducting Phase 3 studies in the field, the future role of allergen exposure chambers in AIT studies and specific considerations in performing AIT studies in the paediatric population. Finally, the group highlighted the forthcoming EAACI guidelines and their particular importance for the standardization of practice in the treatment of allergies. This review presents a comprehensive insight into those panel discussions and highlights unmet needs and also possible solutions to them for the future.

Advances in allergen immunotherapy: aiming for complete tolerance to allergens.

Allergen-specific immunotherapy (AIT) has been used for more than 100 years as a tolerance-inducing therapy for allergic diseases and represents a potentially curative method of treatment. AIT functions through multiple mechanisms, including regulating T and B cell responses, changing antibody isotypes, and decreasing mediator release and migration of eosinophils, basophils, and mast cells to affected tissues. Despite the relative success of AIT, attempts are being made to improve this therapy in order to overcome problems in standardization, efficacy, safety, long duration of treatment, and costs. These have led to the development of biotechnological products with successful clinical results.

Advances in subcutaneous immunotherapy

Current limitations in subcutaneous immunotherapy (SCIT) include the length of time required to achieve tolerance as well as the potential for systemic side-effects. Advances in allergen immunotherapy include targeted therapies to B-cell and T-cell pathways that can lead to more rapid desensitization and potentially the prevention of allergic disease. Novel molecularly engineered compounds and delivery vehicles allow for rapid and efficient desensitization. Combination with immune modifiers, treatment with epitope-based compounds, and hypoallergenic recombinant vaccines have the potential to improve immunogenicity while limiting systemic side-effects. Advances in SCIT create new therapeutic opportunities for patients to improve safety, efficacy, and compliance. Concepts using epitope-based immunotherapy and carrier-fusion peptides have the potential to induce tolerance quickly via selective B-cell and T-cell pathways.

Allergen immunotherapy

To provide a historical perspective on the development of allergen immunotherapy and to describe the progress that has been made in both the clinical application and the scientific understanding of this therapeutic technique in the 100 years since its inception. Although allergen immunotherapy has been part of allergy practice for a century, it is only in relatively recent years that the cellular and molecular mechanisms which underlie its clinical efficacy have been elucidated. Most recent studies implicate the T-regulatory cell response as central to the development of a tolerogenic state in response to allergen immunotherapy, with both IL-10 and TGF-β playing crucial roles in the development of this cell subset. The clinical application of immunotherapy continues to advance, with promising contemporary studies noting improved safety and efficacy with pretreatment using omalizumab prior to an immunotherapy program as well as the potential for innate immune system modulation with allergen conjugates which can stimulate pattern recognition receptors such as the toll-like receptors. After 100 years of clinical application, allergen immunotherapy remains the only treatment modality with the potential for long-term immunologic amelioration of atopic diseases. Future treatment advances in allergen immunotherapy will likely harness the increasing power of molecular and genomic medicine to achieve greater allergen specificity, while improving overall efficacy and minimizing the potential for systemic reactions.

Allergen Immunotherapy: A Centenary Celebration

In 1911 and long before the availability of antiallergic drugs, Leonard Noon demonstrated that prophylactic subcutaneous inoculation with a grass pollen extract was effective in suppressing immediate conjunctival sensitivity to grass pollen.1 Noon’s coworker, John Freeman, continued to practice immunotherapy and in 1930 published the first rush immunotherapy protocol.2 William Frankland, a colleague of Freeman, performed the first controlled clinical trial of grass pollen immunotherapy in 1954.3 He used a whole grass pollen extract that was compared with its partially purified proteins, the corresponding ultrafiltrate that contained no protein and a phenol-containing diluent. Both the whole extract and the purified grass pollen proteins were effective compared with the ultrafiltrate and the diluent control alone (Fig. 1). Frankland’s study established a firm scientific foundation for the practice of allergen immunotherapy. Noon, Freeman, and Frankland were all physicians at St. Mary’s Hospital, Paddington, now affiliated to Imperial College London, United Kingdom. Frankland in his 99th year continues to practice and play a major role in the allergy community; much admired and respected by his colleagues, he represents our centenary link with the origins of the practice of immunotherapy (Fig. 2). Major advances in allergen immunotherapy have resulted from parallel studies performed in the United States. Lowell and Franklin in 1964 were the first to clearly demonstrate that a single allergen (ragweed) in a multiallergen mixture was effective in reducing seasonal allergic symptoms.4 Philip Norman and Larry Lichtenstein in 1978 convincingly demonstrated the allergen-specificity of ragweed immunotherapy in patients with dual sensitivity to ragweed and grass pollen.5 Johnstone first highlighted the possibility that immunotherapy in children might confer protection against development of asthma,6 a concept supported by the more recent Preventive Allergy Treatment (PAT) study that identified a 2–3 fold risk reduction for developing asthma after 3 years treatment in children with seasonal pollinosis, protection that persisted for a further 7 years after discontinuation of immunotherapy.7 Hunt and colleagues8 demonstrated the efficacy of purified venom over whole insect body extract and placebo in patients with anaphylaxis to the stings of hymenoptera. Studies9 have confirmed the dose-dependency of allergen immunotherapy whereas the long-term benefits of allergen immunotherapy, with persistence of efficacy for several years after discontinuation10 have been illustrated for both venom11 and grass pollen immunotherapy, the latter both for subcutaneous and sublingual routes of therapy.12 Our increasing knowledge of the mechanisms of immunotherapy has informed both novel approaches and the development of putative biomarkers that might predict the clinical response to immunotherapy. Prausnitz and Kustner13 published in 1921 that a serum factor (‘reagin’) could transfer immediate allergen sensitivity as shown by skin testing was followed Robert Cooke’s observation in 1935 that serum obtained after pollen immunotherapy could confer ‘immunity and hypersensitivity.’14 These seminal observations long preceded the discovery of IgE antibody as reagin by the Ishizakas,15 Johansson and Bennich,16 and the concept of IgG ‘blocking antibodies.’17 The suppressive effect of ragweed immunotherapy on nasal eosinophils as a local marker of allergic inflammation was shown by Creticos in 1984,18 whereas Passalacqua and Canonica similarly demonstrated decreased local eosinophilia and adhesion molecule expression during mite sublingual immunotherapy.19 Warner in 197820 and Rak21 in 1991 observed decreases in allergeninduced late asthmatic responses and associated bronchial inflammation, respectively, in children and adults. A link between altered T-cell responses and immunotherapy was first shown by Rocklin22 whereas the critical role of regulatory T cells and IL-10 was highlighted by Akdis and colleagues.23 The concept of immune deviation of allergenspecific TH2 responses in favor of TH1 responses in both the periphery and in target organs has developed in parallel.24–26 From the Royal Brompton National Heart & Lung Institute, London; and National Jewish Health, Denver, CO. Correspondence to: Stephen R. Durham, MA, MD, FRCP, Royal Brompton Hospital and Imperial College, Dovehouse Street, London SW3 6LY United Kingdom. Telephone: 442073518024. Fax: 442073497780. E-mail: s.durham@ imperial.ac.uk. Copyright © 2011 by World Allergy Organization FIGURE 1. Table II shows the results of the first immunotherapy controlled trial, as published in: Frankland AW, Augustin R. Prophylaxis of summer hay-fever and asthma: a controlled trial comparing crude grass-pollen extracts with the isolated main protein component, The Lancet, May 24, 1954.